Identification of a mutation in COL4A5 causative for X-linked Alport syndrome in the domestic dog and analysis of gene expression in the kidneys of affected and nonaffected siblings

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Title: Identification of a mutation in COL4A5 causative for X-linked Alport syndrome in the domestic dog and analysis of gene expression in the kidneys of affected and nonaffected siblings
Author: Cox, Melissa Luanne
Abstract: The domestic dog , Canis lupus familiaris , plays many roles in the lives of humans . Additionally , the dog is recognized for its potential as a model for many human hereditary diseases . Thus , the genetics and genomics of the dog are being studied extensively in order to facilitate its use as a model , as well as to help the dog for its own sake . As part of this research effort , our laboratory has added type I markers (i .e . , the acidic and basic keratins , c -kit , type I and IV collagens , and the gene encoding uromodulin ) to the emerging map of the canine genome . The mapping of genes , particularly those in large gene families such as the collagens , is valuable because it rapidly increases the density of gene loci on the map and provides insight regarding conservation of synteny between the dog and other mammals . The major focus of work reported here is the genetics of X -linked Alport syndrome (XLAS ) , a terminal renal disease that affects the human and the dog . The disease results from mutations in COL4A5 , a type IV collagen gene . Reported here are the 1 ) sequencing and mapping of the canine cDNA encoding uromodulin , 2 ) mapping of the type I and type IV collagen genes , 3 ) sequencing of the full -length cDNA of canine COL4A5 , 4 ) identification of a 10 bp deletion in COL4A5 , causative for XLAS in our colony of mixed breed dogs , 5 ) development of a genetic test for identification of affected and carrier dogs in the colony and 6 ) assessment of gene expression in the kidneys of normal and XLAS -dogs . This assessment was performed using a canine -specific oligonucleotide microarray . XLAS dogs demonstrated up -regulation of many genes involved in extracellular matrix reorganization , cell structure , and immune response , as expected in a glomerulopathy with tubulointerstitial nephritis . Trends were verified by quantitative RT -PCR . A review of the current status of canine genetics research , and current understanding of hereditary diseases in the dog , concludes this dissertation .
URI: http : / /hdl .handle .net /1969 .1 /244
Date: 2004-09-30

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Identification of a mutation in COL4A5 causative for X-linked Alport syndrome in the domestic dog and analysis of gene expression in the kidneys of affected and nonaffected siblings. Available electronically from http : / /hdl .handle .net /1969 .1 /244 .

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